Pharmacological modulation of telomere length in cancer cells for prevention and treatment of cancer

Abstract

Acyclic nucleoside analogs such as acyclovir, ganciclovir, penciclovir and the corresponding pro-drugs, i.e., valacyclovir, valganciclovir and famciclovir, respectively have been identified as inhibitors or antagonists of both telomerase (encoded by TERT) and reverse transcriptase encoded by L-1 (LINE-1) RT, and as useful for treating or preventing cancers induced or mediated by the two enzymes. Method of treating or preventing such cancers in patients involves administration of a therapeutically effective amount of a composition having an inhibitor or antagonist of the reverse transcriptases in cells of the patients. The inhibitor or antagonist blocks lengthening of telomeres in telomerase positive and telomerase negative cells. Methods and kits for detecting pathologically proliferating cells expressing TERT and L1RT are also disclosed.

Description

[0001]This application claims the benefit of U.S. Provisional Application No. 60 / 682,110 filed May 18, 2005, and the text of application 60 / 682,110 is incorporated by reference in its entirety herewith.FIELD OF THE INVENTION[0002]The present invention is directed to the field of cancer therapy. Specifically, the present invention relates to the regulation of telomere elongation in cancer cells. More particularly, the present invention relates to the use of acyclic nucleoside analogs for treating or preventing cancers.BACKGROUND OF THE INVENTION[0003]An asymmetry in the synthesis of leading and lagging DNA strands creates the “end problem” for replication of linear genomes.1 To overcome this problem, eukaryotic chromosomes have specialized end structures, telomeres, consisting of TTAGGG repeats.2 Telomerase3,4 is a ribonucleoprotein enzyme that elongates telomeres and therefore maintains chromosomal stability in majority of cancer cells during cell doubling5. The gradual loss of DNA ...

AI Technical Summary

Benefits of technology

[0010]As telomeres are involved in controlling the cell cycle, cell replication and aging, nucleoside analog containing compositions of the present invention can prevent or control uncontrolled cell growth and the immortality of tumor cells. The compositions of the present invention find particular utility in the treatment of cell proliferative disorders, and in particular human tumors characterized as having telomeres maintained or elongated by telomerase or L1RT.

[0012]Interference with telomere elongation or maintenance may either directly result in cell death or may potentiate the effects of chemotherapeutic agents that ultimately kill cells through apoptosis. In particular, the invention provides a method for inhibiting proliferation of telomerase / L1RT expressing cells having potential for continuous increase in cell number by administering the compositions containing the acyclic nucleoside analogs of the present invention. Administration of a nucleoside analog can be achieved by any desired means well known to those of ordinary skill in the art.

[0013]In an embodiment of the invention, a method for prevention of a cancer characterized by expression of telomerase or L1RT in cells of a mammal or a subject (e.g. a human) in need thereof is provided. The preventive method involves administration of a therapeutically effective amount of a composition to the mammal. The composition has a telomerase inhibitor or antagonist of the present invention. The inhibitor or antagonist blocks the lengthening of telomeres in telomerase-positive / telomerase-positive cells, thereby inhibiting proliferation of telomerase expressing cells. The inhibitor is an acyclic nucleoside analog or a pharmaceutically acceptable salt of such an analog or a liquid or solid food material that is enriched with the inhibitor or antagonist. The food product can be, for example, a functional food in the form of butter, margarine, biscuits, bread, cake, candy, confectionery, yogurt or another fermented milk product, or cereal suitable for consumption by humans. Alternatively, it can be a nutritional supplement, a nutrient, a pharmaceutical, food, a nutraceutical, a health food and / or a designer food. Periodically, the human is tested for the presence of telomerase positive cells. The use of inhibitor or antagonist may be stopped once the telomerase positive cells are no longer detected in the mammal.

Problems solved by technology

Currently, there are no therapeutic compositions in use that are based on nucleoside analogs that are acyclic, anti-telomerase, anti-L1RT and antineoplastic.

Once the telomere length shortens to a critical length, the tumor will go into crisis and eventually die.

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